Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2

doi:10.1016/j.molcel.2016.01.015

. 2016 Feb 18;61(4):520-534.

doi: 10.1016/j.molcel.2016.01.015. Epub 2016 Feb 4.

Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2

Roxana S Redis¹, Luz E Vela², Weiqin Lu³, Juliana Ferreira de Oliveira⁴, Cristina Ivan⁵, Cristian Rodriguez-Aguayo¹, Douglas Adamoski⁴, Barbara Pasculli¹, Ayumu Taguchi⁶, Yunyun Chen⁷, Agustin F Fernandez⁸, Luis Valledor⁹, Katrien Van Roosbroeck¹, Samuel Chang¹, Maitri Shah¹, Garrett Kinnebrew¹⁰, Leng Han¹¹, Yaser Atlasi¹², Lawrence H Cheung¹, Gilbert Y Huang¹, Paloma Monroig¹, Marc S Ramirez¹³, Tina Catela Ivkovic¹⁴, Long Van², Hui Ling¹, Roberta Gafà¹⁵, Sanja Kapitanovic¹⁶, Giovanni Lanza¹⁵, James A Bankson¹³, Peng Huang⁶, Stephen Y Lai⁷, Robert C Bast¹, Michael G Rosenblum¹, Milan Radovich¹⁰, Mircea Ivan¹⁷, Geoffrey Bartholomeusz¹, Han Liang¹⁸, Mario F Fraga¹⁹, William R Widger², Samir Hanash²⁰, Ioana Berindan-Neagoe²¹, Gabriel Lopez-Berestein²², Andre L B Ambrosio⁴, Sandra M Gomes Dias⁴, George A Calin²³

Affiliations

¹ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Biology & Biochemistry, University of Houston, Houston, TX 77204, USA.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas 13083-100, Brazil.
⁵ Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo 33006, Spain.
⁹ Department of Organisms and Systems Biology, University of Oviedo, Ovideo 33006, Spain.
¹⁰ Department of Surgery, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹¹ Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
¹² Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3015, the Netherlands.
¹³ Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb 10000, Croatia.
¹⁵ Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
¹⁶ Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb 10000, Croatia.
¹⁷ Department of Medicine, Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹⁸ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁹ Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Asturias 33424, Spain.
²⁰ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
²¹ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca 400012, Romania; Department of Functional Genomics, The Oncology Institute, Cluj-Napoca 400015, Romania.
²² Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
²³ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: gcalin@mdanderson.org.

PMID: 26853146
PMCID: PMC4982398
DOI: 10.1016/j.molcel.2016.01.015

Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2

Roxana S Redis et al. Mol Cell. 2016.

. 2016 Feb 18;61(4):520-534.

doi: 10.1016/j.molcel.2016.01.015. Epub 2016 Feb 4.

Authors

Affiliations

¹ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
² Department of Biology & Biochemistry, University of Houston, Houston, TX 77204, USA.
³ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas 13083-100, Brazil.
⁵ Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Head & Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Cancer Epigenetics Laboratory, Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, Oviedo 33006, Spain.
⁹ Department of Organisms and Systems Biology, University of Oviedo, Ovideo 33006, Spain.
¹⁰ Department of Surgery, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹¹ Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.
¹² Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam 3015, the Netherlands.
¹³ Department of Imaging Physics, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁴ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb 10000, Croatia.
¹⁵ Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44121, Italy.
¹⁶ Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruder Boskovic Institute, Zagreb 10000, Croatia.
¹⁷ Department of Medicine, Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
¹⁸ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁹ Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Asturias 33424, Spain.
²⁰ Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
²¹ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Research Center for Functional Genomics, Biomedicine and Translational Medicine, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca 400012, Romania; Department of Functional Genomics, The Oncology Institute, Cluj-Napoca 400015, Romania.
²² Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
²³ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: gcalin@mdanderson.org.

PMID: 26853146
PMCID: PMC4982398
DOI: 10.1016/j.molcel.2016.01.015

Erratum in

Mol Cell. 2016 Feb 18;61(4):640

Abstract

Altered energy metabolism is a cancer hallmark as malignant cells tailor their metabolic pathways to meet their energy requirements. Glucose and glutamine are the major nutrients that fuel cellular metabolism, and the pathways utilizing these nutrients are often altered in cancer. Here, we show that the long ncRNA CCAT2, located at the 8q24 amplicon on cancer risk-associated rs6983267 SNP, regulates cancer metabolism in vitro and in vivo in an allele-specific manner by binding the Cleavage Factor I (CFIm) complex with distinct affinities for the two subunits (CFIm25 and CFIm68). The CCAT2 interaction with the CFIm complex fine-tunes the alternative splicing of Glutaminase (GLS) by selecting the poly(A) site in intron 14 of the precursor mRNA. These findings uncover a complex, allele-specific regulatory mechanism of cancer metabolism orchestrated by the two alleles of a long ncRNA.

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Figures

Figure 1. *CCAT2* regulates cancer metabolism *in vitro* and *in vivo*
(A) Glucose uptake, lactate production and oxygen consumption assays in HCT116 stable clones (E – empty control vector, OC1 and OC3 – *CCAT2*-overexpressing – GG genotype). (B) Glucose uptake, lactate production and oxygen consumption assays in KM12SM cells with *CCAT2* downregulation (GT-genotype). (C) Whole cell lysate *Glutaminase* activity measured in HCT116 *CCAT2*-overexpressiong G- or T-allele and control cells. (D) Partial least squares discriminant analysis (sPLS-DA) of HCT116 cells stably overexpressing *CCAT2* with either G - or T-allele, and control cells (E – empty vector) *in vitro* allowed an adequate classification of the different cell lines according to its metabolome*. (E) Xenograft tumors derived from the same cell lines were also correctly classified by sPLS-DA analysis. Results are presented as normalized mean values ± SD. See also Fig. S1 and Table S1. *sPLS-DA algorithm allows the classification of the samples based on the different abundances of each metabolite trying to find the maximum covariance between treatments and metabolome, in this way finding the most important metabolites for explaining the different effects of the treatments.

**Figure 2. *CCAT2* induces the preferential splicing of GAC**
(A) Western Blot analysis of GAC, KGA in HCT116 *CCAT2*-overexpressing (OC1 and OC3) and control cells. (B) RT-qPCR assessing the mRNA expression of GAC and KGA in HCT116 *CCAT2*-overexpressing cells (OC1 and OC3) and control cells. (C) Western Blot analysis of GAC, KGA in KM12SM cells with *CCAT2* downregulation. (D) Western Blot analysis of GAC, KGA in HCT116 stably overexpressing *CCAT2* G- or T-allele and control cells. (E) Fluorescence microscopy images of HCT116 stable clones (E – empty control vector, OC1 and OC3 – *CCAT2*-overexpressing) transfected with the RG6 Intron 14 vector and the analysis of the EGFP/dsRED ratio. (F) Fluorescence microscopy images of HCT116 *CCAT2* G-allele and T-allele transfected with the RG6 intron 14 vector and the analysis of the EGFP/dsRED ratio. Results are presented as normalized mean values ± SD. See also Fig. S2 and **Table 2.**

**Figure 3. CFIm protein complex binds *GLS* pre-mRNA**
(A) Western Blot analysis of CFIm25, GAC and KGA in HCT116 OC1 and KM12SM cells transiently transfected with siRNA for NUDT21, GLS (targeting the coding sequence shared by the two isoforms) and siRNA control. (B) RT-qPCR assessing the GAC/KGA mRNA ratio in HCT116 *CCAT2*-overexpressing cells (OC1 and OC3) and control cells (E) with modulated CFIm25 expression (C) Western Blot analysis of GAC and KGA in HCT116 OC1 cells with transient blockage of CFIm25 binding motifs (UGUA) by antisense oligonucleotides (ASOs). Schematic representation of the mechanism is presented below. (D) RT-qPCR assessing the fold enrichment of *GLS, CCAT2, NEAT1* and *GAS5* RNA bound to CFIm25 protein (RNA immunoprecipitation). Data are presented as fold enrichment ratios between control HCT116 cells (E) and *CCAT2*-overexpressing G- or T-allele. RT-qPCR assessing the fold enrichment of *GLS* mRNA (E) and *CCAT2* (F) bound to CFIm25 and CFIm68 in HCT116 cells *CCAT2*-overexpressing G- or T-allele and control cells (E). (G) Fluorescence microscopy images of KM12SM cells transfected with siNUDT21 and scr, followed by transfection with the RG6 intron 14 vector, and the analysis of the EGFP/dsRED ratio. Results are presented as normalized mean values ± SD. See also Fig. S3 and **Table 2.**

**Figure 4. The rs6983267 SNP afftects the interaction of *CCAT2* with the CFIm protein complex**
(A) Western Blot analysis of the proteins pulled down with the MS2-*CCAT2* vectors (G, T, A, C and DEL) showing the presence of CFIm25 for the G allele and CFIm68 for the T-allele. (B) Northern Blot analysis showing the presence of *CCAT2* and intron 14 (600bp fragment) in the lysate pulled down with TALON resin (upper panel). Western Blot analysis showing the presence of the His₆-tagged CFIm complex in the lysate pulled down with the TALON resin (lower panel). (C) Northern Blot analysis showing the presence of *CCAT2* and intron 14 (600bp fragment) in the lysate pulled down with Streptavidin beads. Lane 1 marked with the star symbol is identical to lane 3 in Fig. S4D. Schematic illustration of the interaction of *CCAT2* with *GLS* pre-mRNA (representation is not at scale) (D) Northern Blot analysis showing the presence of *CCAT2* and intron 14 (600bp fragment) in the lysate pulled down with Streptavidin beads (upper panel). Western Blot analysis showing the presence CFIm25, monomer (26 kDa) and dimer (64 kDa), and His₆-tagged CFIm68 (38 kDa) (lower panel). (E, F) AFM images of CCAT2:CFIm:intron 14 quaternary complex including either *CCAT2* T-allele (E) or *CCAT2* G-allele (F). See also Fig. S4, S5 and **Table 3.**

**Figure 5. GLS promotes *in vivo* metastases and *in vitro* cell proliferation and migration**
(A) Migration of HCT116 OC1 cells (GG genotype) treated with the inhibitor 968 and DMSO (**left panel**) and with siGLS and scrambled siRNA (**right panel**). (B) Migration of KM12SM cells (GT genotype) with stable downregulation of GAC. KM12SM shGFP cells represent the control cells. (C) Number of the lung micrometastases for two groups (shGFP – 4 mice and shGAC – 4 mice) assessed by IHC (**left panel**). IHC images showing micrometastases in the three groups and images showing the presence or absence of lung metastases for mice injected in the tail-vein with KM12SM shGFP and shGAC cells, respectively (**right panel**). (**D, E**) Growth curves for HCT116 OC1 and control cells (GG genotype) treated with DMSO (control) or the GLS allosteric inhibitor 968 (10 μM) (D) and KM12SM cells (GT genotype) with stable downregulation of GAC (E). Glutamine and glutamate concentration in the media relative to the empty well 24 hours after seeding HCT116 *CCAT2*-overexpressing cells (OC1 – GG genotype) transfected with siRNA against *NUDT21* and scrambled (F) and ASOs for inhibiting the binding sites of CFIm25 (G). Results are presented as normalized mean values ± SD. See also Fig. S6 and **Table 4.**

**Figure 6. *CCAT2*, *NUDT21* (CFIm25), *CPSF6* (CFIm68) and *GLS* (GAC and KGA) expression pattern in TCGA dataset and CRC patient samples**
(**A, B, C** and D) Analysis of *NUDT21, CPSF6, GAC* and *KGA* mRNA expression in TCGA RNA-Seq colon cancer sample set. (E). Association of GAC mRNA expression with the genotypes (GG, GT and TT) of the rs6983267 SNP for CRC patients (TCGA RNA-Seq dataset). (F) Western Blot analysis of CFIm25, GAC and KGA expression in paired CRC samples (*Patient cohort #1)*. (G) RT-qPCR analysis for *CCAT2* in the same paired CRC samples (*Patient cohort #1).* Results are presented as normalized mean values ± SD. See also Fig. S7.

**Figure 7. *CCAT2* gene signature in colon cancer patients (TCGA dataset)**
Genes associated with *CCAT2* were analyzed by Gene Set Enrichment Analysis (GSEA) (A) and Ingenuity Pathway Analysis (IPA - Qiagen) (B). Relevant examples for each analysis are presented in panels (A) and (B). (C) Table containing the pathways significantly associated with *CCAT2* expression and rs6983267 genotype (FDR q-val<0.25 and Nom p-val<0.05). Pathways that were positively correlated are marked with red and the ones that are negatively correlated are marked with blue. Highlighted in green are the pathways found common between GSEA analysis and the Affymetrix HTA 2.0 pathways analysis. See also Fig. S7 and Table S4.

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References

1. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. - PMC - PubMed
1. Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435–446. - PMC - PubMed
1. Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nature Cell Biology. 2015;17:351–359. - PMC - PubMed
1. Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, Cheng PF, Anderson S, Ulrich M, Hurley JB, et al. Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis. Cancer Cell. 2015;27:271–285. - PMC - PubMed
1. Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, Pereira HM, Garratt RC, Dias SM, Ambrosio AL. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:1092–1097. - PMC - PubMed

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[1] Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. - PMC - PubMed

[2] Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. - PMC - PubMed

[3] Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435–446. - PMC - PubMed

[4] Bester AC, Roniger M, Oren YS, Im MM, Sarni D, Chaoat M, Bensimon A, Zamir G, Shewach DS, Kerem B. Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell. 2011;145:435–446. - PMC - PubMed

[5] Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nature Cell Biology. 2015;17:351–359. - PMC - PubMed

[6] Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nature Cell Biology. 2015;17:351–359. - PMC - PubMed

[7] Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, Cheng PF, Anderson S, Ulrich M, Hurley JB, et al. Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis. Cancer Cell. 2015;27:271–285. - PMC - PubMed

[8] Carroll PA, Diolaiti D, McFerrin L, Gu H, Djukovic D, Du J, Cheng PF, Anderson S, Ulrich M, Hurley JB, et al. Deregulated Myc Requires MondoA/Mlx for Metabolic Reprogramming and Tumorigenesis. Cancer Cell. 2015;27:271–285. - PMC - PubMed

[9] Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, Pereira HM, Garratt RC, Dias SM, Ambrosio AL. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:1092–1097. - PMC - PubMed

[10] Cassago A, Ferreira AP, Ferreira IM, Fornezari C, Gomes ER, Greene KS, Pereira HM, Garratt RC, Dias SM, Ambrosio AL. Mitochondrial localization and structure-based phosphate activation mechanism of Glutaminase C with implications for cancer metabolism. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:1092–1097. - PMC - PubMed

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Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2

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Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2

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